The biological activity of chiral chemical compounds often depends upon their absolute stereochemical configuration, since a living body presents a highly enantioselective environment. Therefore, many racemic compounds show significant enantiomeric selectivity in pharmacokinetics and pharmacodynamics. Often a single enantiomer of a racemic mixture has a desired therapeutic effect while the enantiomer of opposite configuration may be ineffective or may even produce undesirable side effects. Awareness of this phenomenon intensified when the teratogenic effects of the drug thalidomide, once used as an anti-nausea medication for pregnant women, emerged in the 1960s. Thalidomide and many other chiral drugs had been sold for years as racemic mixtures. In 1992, the U.S. Food & Drug Administration (FDA) issued a policy on stereoisomeric drugs. Although the FDA allows racemates to be sold, the individual enantiomers must be characterized pharmacologically and toxicologically. It has been estimated that in 2006, 80% of small-molecule drugs approved by FDA were chiral and 75% were single enantiomers and, with increasing evidence of problems related to stereoselectivity in drug action, enantioselective analysis by chromatographic methods has become the focus of intensive research of separation scientists.
High performance liquid chromatography (HPLC) utilizing chiral stationary phases is the most popular method for determining the enantiomeric purity of chemical compounds on analytical columns or for isolating enantiomers on preparative columns. In the chemical and pharmaceutical Industries methods development often includes screening chiral compounds and potential impurities on analytical columns with numerous chiral phases.
Conventionally, chromatographic media utilizing the chirality of natural polysaccharide derivatives are widely known. Most commonly, the polysaccharide derivative is an ester derivative or carbamate derivative of cellulose or amylose. For example, U.S. Pat. No. 4,818,394 to Okamoto et al. discloses and claims various cellulose tribenzoates for the chromatographic resolution of optical isomers and U.S. Pat. No. 5,489,387 to Namikoshi et al. describes a chromatographic separation medium comprising cellulose tris-3-(3-pydridyl)acrylate. U.S. Pat. No. 7,223,334 to Okamoto et al. describes separating agent for enantiomeric isomers using cellulose tris(cyclohexylcarboxylate), cellulose tris(cyclopentylcarboxylate) or cellulose tris(cycloadamantylcarboxylate), while U.S. Pat. No. 7,156,989 to Okamoto et al. describes separating agents for enantiomeric isomers comprising amylose tris 5-indanylcarbamate. Also, U.S. Pat. No. 5,472,599 to Shibata discloses a chromatographic separating agent comprising dextran tribenzoates and U.S. Pat. No. 5,639,824 to Okamoto describes a chromatographic medium consisting of a chemically bonded body comprising a support and a highly substituted oligomeric cyclodextran derivative having a 3,5-dimethylphenylcarbamate constituent.
Although many polysaccharide derivatives have proven useful as chromatographic media, it is well known that such natural polysaccharides show considerable variation with respect to parameters such as molecular weight, proportions of the sugar monomer constituents, degree of branching and particular linkage types. In fact, few natural polysaccharides, if any, are monodisperse. Furthermore, polysaccharides such as cellulose, chitosan, amylose and the like, which are derived from different species or from different sources within a species, show significant variation in structure, chemical properties and molecular weight. Such variability of natural polysaccharides causes problems in the production of consistent chromatographic media and renders the chromatographic methods based on such media less that ideal. Since the synthetic, non-polysaccharide, carbohydrate polyethers of the present invention are essentially monodisperse and uniform in structure, the chromatographic media produced there from are consistent with potentially little or no batch-to-batch variability.
Many stationary phases for HPLC columns utilize polysaccharide derivatives supported on carriers such as alumina, zirconia or silica gel for the purposes of increasing the packing ratio of the separating agent into a column, facilitating handling, enhancing mechanical strength, and the like. The synthetic non-polysaccharide carbohydrate polymers of the present invention are amenable to the known techniques and methods employed to support the chiral selector on such carriers.
The derivatives of natural polysaccharides presently used as chromatographic stationary phases are most commonly coated onto carriers in thick layers, which results in processes wherein transport is slow and peaks are substantially broad. Furthermore, the use of natural high polymers or their derivatives as stationary phases requires the use of carrier particles of large pore-size and since such particles are fragile the operating pressure a high-pressure liquid chromatography (HPLC) system is limited. Therefore, there exists a need for improved non-polysaccharide polymeric materials for use in stationary phases effective for chromatographic separations via a variety of techniques, wherein such stationary phases have controllable and reproducible manufacturability.
There exists a need for chromatographic media that may prepared by methods that allow for a high degree of control of all molecular, chemical and physical properties of the stationary phase.
There exists a need for method for reproducibly providing non-polysaccharide based materials with control of relative hydrophilicity/hydrophobicity.
There exists a need for stationary phases effective for chromatographic separation that may be conveniently modified or custom synthesized to accommodate specific separation requirements.
There exists a need for low molecular weight non-polysaccharide based materials for use as stationary phases of chromatographic media that allow rapid mass transport and high capacity.
There also exists a need for new non-polysaccharide stationary phases effective in chromatographic separation of enantiomers to address increasing demand in the chemical and pharmaceutical industries.
The present invention addresses these and other needs.